Multiple myeloma is a tumor resulting from malignant transformation of plasma cells, immunocytes in the bone marrow due to genetic abnormalities or the like. These malignant plasma cells (myeloma cells) migrate through the bloodstream and accumulate in the bone marrow where they proliferate, causing bone damage, hypercalcemia, renal failure, anemia, neuropathy and infections. Bone damage is caused by rapid proliferation of myeloma cells and resorption and breakdown of bones by osteoclasts stimulated by interleukin-6 (IL-6) which is released by myeloma cells. Bone damage can also cause the level of calcium in the bloodstream to rise, a condition called hyprecalcemia. Hypercalcemia injures the kidneys, resulting in reduced calcium excretion, increased urine production and the potential for dehydration. As myeloma cells crowd out normal cells in the bone marrow, the production of normal blood cells is also impaired. A reduction in leukocyte count can increase the high risk of infections due to immunodeficiency, and decreased erythrocyte counts can result in anemia. A reduction in platelets can prevent normal blood clotting. In addition, excess globulin and light chain proteins produced by myeloma cells can thicken the blood (hyperviscosity syndrome) and can cause circulatory problems in the kidneys. These proteins can also damage the kidneys and cause acute renal failure and chronic renal failure. Invasion of myeloma cells into the spinal canal can cause pain through spinal cord compression and can progress to paralysis. Accumulation of the amyloid protein derived from the M proteins secreted from myeloma cells can injure peripheral nerves (amyloidosis). Because multiple myeloma affects many tissues and organs in patients, the symptoms and signs are variable.
As mentioned above, multiple myeloma is a lethal disease associated with various complications, and there is no treatment that results in complete and permanent recovery from the disease with no or little side effect so fart. Therefore, there is a need for new treatment methods for multiple myeloma, and treatment of multiple myeloma with low molecular weight compounds having growth inhibitory effects on myeloma cells has been studied. However, no low molecular weight compounds having satisfying therapeutic effect on multiple myeloma have been found so far (Non-Patent Documents 1 to 5).
Meanwhile, pyrazole compounds are reported to have various biolactivities, and many pyrazole-based compounds have been developed for agricultural and medicinal use (Patent Document 1 and 2 and Non-Patent Documents 6 to 8).